Fungal melanin suppresses airway epithelial chemokine secretion through blockade of calcium fluxing

Jennifer L. Reedy, Kirstine Nolling Jensen, Arianne J. Crossen, Kyle J. Basham, Rebecca A. Ward, Christopher M. Reardon, Hannah Brown Harding, Olivia W. Hepworth, Patricia Simaku, Geneva N. Kwaku, Kazuya Tone, Janet A. Willment, Delyth M. Reid, Mark H. T. Stappers, Gordon D. Brown, Jayaraj Rajagopal and Jatin M. Vyas ()
Additional contact information
Jennifer L. Reedy: Massachusetts General Hospital
Kirstine Nolling Jensen: Massachusetts General Hospital
Arianne J. Crossen: Massachusetts General Hospital
Kyle J. Basham: Massachusetts General Hospital
Rebecca A. Ward: Massachusetts General Hospital
Christopher M. Reardon: Massachusetts General Hospital
Hannah Brown Harding: Massachusetts General Hospital
Olivia W. Hepworth: Massachusetts General Hospital
Patricia Simaku: Massachusetts General Hospital
Geneva N. Kwaku: Massachusetts General Hospital
Kazuya Tone: Institute of Medical Sciences
Janet A. Willment: Institute of Medical Sciences
Delyth M. Reid: Institute of Medical Sciences
Mark H. T. Stappers: Institute of Medical Sciences
Gordon D. Brown: Institute of Medical Sciences
Jayaraj Rajagopal: Massachusetts General Hospital
Jatin M. Vyas: Massachusetts General Hospital

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract Respiratory infections caused by the human fungal pathogen Aspergillus fumigatus are a major cause of mortality for immunocompromised patients. Exposure to these pathogens occurs through inhalation, although the role of the respiratory epithelium in disease pathogenesis has not been fully defined. Employing a primary human airway epithelial model, we demonstrate that fungal melanins potently block the post-translational secretion of the chemokines CXCL1 and CXCL8 independent of transcription or the requirement of melanin to be phagocytosed, leading to a significant reduction in neutrophil recruitment to the apical airway both in vitro and in vivo. Aspergillus-derived melanin, a major constituent of the fungal cell wall, dampened airway epithelial chemokine secretion in response to fungi, bacteria, and exogenous cytokines. Furthermore, melanin muted pathogen-mediated calcium fluxing and hindered actin filamentation. Taken together, our results reveal a critical role for melanin interaction with airway epithelium in shaping the host response to fungal and bacterial pathogens.

Date: 2024
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DOI: 10.1038/s41467-024-50100-x

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